Histone Deacetylase 3 regulates the ontogeny and maintenance of tissue-resident macrophages

Document Type

Conference Proceeding

Publication Date


Publication Title

J Invest Dermatol


Tissue-resident macrophages (TRMs) are essential for tissue homeostasis, immune-surveillance, and resolution of inflammation, and contribute to the pathogenesis of cancer, autoimmune, and inflammatory diseases. Most adult TRMs are derived from embryonic yolk sac erythro-myeloid progenitors and self-maintain independently from adult hematopoiesis. A few genes have been recently identified to be required for TRM tissue-specific development. However, the master regulator that centrally controls TRM ontogeny remains a mystery. Using a fate-mapping strategy, here we report that conditional deletion of histone deacetylase 3 (HDAC3) in mice essentially abrogates epidermal Langerhans cells and TRMs in dermis, lung, kidney, and heart at embryonic stage and after birth. In contrast, HDAC3 deletion promotes liver TRM ontogeny, while without significant effects on brain TRM microglia. Using lung TRM alveolar macrophage (AM) as a model, we further indicate that HDAC3 controls metabolism and cell death, at least by directly targeting PPAR-γ during AM embryonic development. Moreover, single-cell RNA sequencing identifies four distinct AM sub-clusters and lack of HDAC3 dysregulates AM functions in a cluster-specific manner. Overall, this is the first study to demonstrate that HDAC3 serves as a key epigenetic regulator of embryonic TRM ontogeny and maintenance in a spatial- and tissue-specific manner. Not only do these findings provide a new conceptual framework for our understanding of epigenetic regulation in TRM ontogeny and homeostasis, they also shed light on HDAC3 as a potential therapeutic target for TRM-based intervention in cancer and autoimmune diseases.





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